Previous evidence has indicated that an intact centrosome is essential for cell cycle progress and that elimination of the centrosome or depletion of individual centrosome proteins prevents the entry into S phase. To investigate the molecular mechanisms of centrosome-dependent cell cycle progress, we performed RNA silencing experiments of two centrosome-associated proteins, pericentriolar material 1 (PCM-1) and pericentrin, in primary human fibroblasts. We found that cells depleted of PCM-1 or pericentrin show lower levels of markers for S phase and cell proliferation, including cyclin A, Ki-67, proliferating cell nuclear antigen, minichromosome maintenance deficient 3, and phosphorylated retinoblastoma protein. Also, the percentage of cells undergoing DNA replication was reduced by >50%. At the same time, levels of p53 and p21 increased in these cells, and cells were predisposed to undergo senescence. Conversely, depletion of centrosome proteins in cells lacking p53 did not cause any cell cycle arrest. Inhibition of p38 mitogen-activated protein kinase rescued cell cycle activity after centrosome protein depletion, indicating that p53 is activated by the p38 stress pathway.
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28 August 2006
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August 28 2006
Inhibition of centrosome protein assembly leads to p53-dependent exit from the cell cycle
Vlastimil Srsen,
Vlastimil Srsen
Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh EH9 3JR, Scotland, UK
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Nicole Gnadt,
Nicole Gnadt
Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh EH9 3JR, Scotland, UK
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Alexander Dammermann,
Alexander Dammermann
Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh EH9 3JR, Scotland, UK
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Andreas Merdes
Andreas Merdes
Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh EH9 3JR, Scotland, UK
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Vlastimil Srsen
Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh EH9 3JR, Scotland, UK
Nicole Gnadt
Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh EH9 3JR, Scotland, UK
Alexander Dammermann
Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh EH9 3JR, Scotland, UK
Andreas Merdes
Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh EH9 3JR, Scotland, UK
Correspondence to Andreas Merdes: [email protected]
A. Dammermann's present address is Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093.
A. Merdes' present address is Centre National de la Recherche Scientifique–Pierre Fabre, 31400 Toulouse, France.
Abbreviations used in this paper: MCM3, minichromosome maintenance deficient 3; PCM-1, pericentriolar material 1; PCNA, proliferating cell nuclear antigen; pRb, retinoblastoma protein.
Received:
June 09 2006
Accepted:
July 25 2006
Online ISSN: 1540-8140
Print ISSN: 0021-9525
The Rockefeller University Press
2006
J Cell Biol (2006) 174 (5): 625–630.
Article history
Received:
June 09 2006
Accepted:
July 25 2006
Citation
Vlastimil Srsen, Nicole Gnadt, Alexander Dammermann, Andreas Merdes; Inhibition of centrosome protein assembly leads to p53-dependent exit from the cell cycle . J Cell Biol 28 August 2006; 174 (5): 625–630. doi: https://doi.org/10.1083/jcb.200606051
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